DESCRIPTION (application abstract) Nanotechnology promises to deliver the needed tools to address one of the major unsolved questions: How are cell components integrated to work in synchrony? Although much work has been put into the chemical integration of cellular process, we believe that mechanical factors are equally important. Cellular responses to mechanical cues, mechanotransduction, determine the shape of the organism and are critical for many functions. Defects in mechanotransduction underlie many diseases such as cancers, immune disorders, genetic malformations, and neuropathies. To understand the roles of force, rigidity and form in regulating cell functions requires the development of detailed quantitative pictures of this machinery at both the single molecule level, describing how single molecules respond to mechanical forces, and at the systems level. Further, we will need an understanding of how forces regulate signaling pathways and gene expression. The tools of nanotechnology and modern cell biology now provide the means to investigate many of the physical aspects of these complex processes at the micro- and nano-meter scale. We feel that the best way to understand mechanotransduction in a quantitative way is to develop an integrated approach, ranging from individual molecules to whole systems. Our team has a wide range of expertise including Cell Biophysics and Nanofabrication, Advanced Fluorescence Microscopy and Image Analysis, Immunology and Supported Bilayer Fabrication, Developmental Biology and Signaling Systems Modeling. All groups have multiple projects underway to address important questions in mechanotransduction. Our preliminary results indicate that many different cells are capable of utilizing similar force-sensing, force-generating and force-bearing systems, which stimulates us to think that for many tasks, cells can use a common tool set and phenotypic differences result from differences in the extent and location of use of one tool versus another. This diverse team of scientists, engineers and mathematicians has the expertise and the capabilities to develop and test models of mechanotransduction at the cell and molecular level. Nanotechnology developed in our group enables us to rapidly screen for the optimal matrix rigidity, form, and spacing needed to elicit a given function. Our plan is to customize these technologies to test important biological and engineering models of cell processes. We are addressing these questions at the single cell level, at the level of cell-cell interactions with a focus on the immune synapse, and at the multicellular level in the development of touch sensation. From an understanding of the molecular mechanisms of mechanotransduction in cells, we can develop models to be tested in the cell-cell and multicellular systems. This research will provide important new approaches to stop metastases, to facilitate wound healing and many other medical problems that depend upon mechanotransduction.